Abstract 818: Preclinical studies of the cabazitaxel nanoformulation MPB-1734 support therapeutic application in chemo-resistant solid tumors and synergistic benefit in combination with immune checkpoint inhibitor
Authors: Yuan Hung Hsu, Chih-Lung Chen, Jhih-Yun Jian, Ming-Cheng Wei, Wen-Yuan Hsieh, Chia-Wen Huang, Yung-Chu Chen, Tzu-Hsin Liao, Shian-Jy Wang
Journal: Cancer Research (2023)

Abstract Background: Cabazitaxel (CBZ) is a second-generation taxane that has the potential to overcome taxane-resistance due to the low affinity for the P-glycoprotein efflux pump. However, with the high systemic toxicity such as neutropenia and hypersensitivity, the clinical use is restricted to patients with metastatic castration-resistant prostate cancer who show progression after docetaxel-based chemotherapy. MPB-1734 is a CBZ nanoformulation which is currently being evaluated as monotherapy in patients with advanced solid tumors in a Phase 1/2a trial (NCT04643418). It is developed to overcome the limitations associated with CBZ application and as potential therapeutic agent for chemo-resistant cancers. This work outlines the results of preclinical studies that support the tumor targeting ability, improved safety profiles, significant therapeutic effect, and synergistic benefit in combination with immune checkpoint inhibitor. Methodology: A series of nonclinical studies of MPB-1734 were conducted including toxicology evaluations in two species and the antitumor activity evaluations in a range of xenograft mice models as cervical cancer (KB), ovarian cancer (OVCAR3) and platinum-resistant human ovarian cancer patient-derived-xenograft (PDX) model (OV0276). The antitumor activity of MPB1734 combined with anti-PD-1 antibody were also evaluated in the syngenetic 4T1 breast cancer mice model. Results: Toxicology evaluations of MPB-1734 demonstrated the safety profiles of CBZ were significantly improved, and the tolerated doses of MPB-1734 are at least 2 folds higher than commercial formulation. An in-vivo tumor targeting study showed that MPB1734 mainly accumulated in the tumor sites, rather than in the vital organs. MPB1734 exhibited a better efficacy compared to commercial formulation in KB and OVCAR3 models. For platinum-resistant PDX model, MPB-1734 demonstrated significant anti-tumor efficacy (TGI:100%, p&amp;lt;0.001). For 4T1 mice model, MPB-1734 combined with anti-PD-1 antibody demonstrated synergistic benefit (TGI: 78.6%) compared to anti-PD-1 antibody monotherapy (TGI: 2.8%) and MPB-1734 monotherapy (TGI: 52.9%). This synergistic benefit may result from increased CD8+ T cells in tumor region after MPB-1734 treatment. Conclusion: MPB-1734 can reduce the major dose-limiting side effect (neutropenia) of CBZ and increase the tolerated dose. With tumor targeting ability, superior antitumor effects were demonstrated as compared with commercial formulation in a range of cancer models. MPB-1734 combined with anti-PD-1 antibody showed synergistic benefit in tumor inhibition. These preclinical results support the potential use of MPB-1734 as therapeutic agent for chemo-resistant cancer with monotherapy or combination therapy with immuno-oncology agents. Citation Format: Yuan Hung Hsu, Chih-Lung Chen, Jhih-Yun Jian, Ming-Cheng Wei, Wen-Yuan Hsieh, Chia-Wen Huang, Yung-Chu Chen, Tzu-Hsin Liao, Shian-Jy Wang. Preclinical studies of the cabazitaxel nanoformulation MPB-1734 support therapeutic application in chemo-resistant solid tumors and synergistic benefit in combination with immune checkpoint inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 818.